Operator-controlled scanning laser procedure designed for large-area epithelium removal

ABSTRACT

Systems and methods for removing an epithelial layer disposed over a stromal layer in a cornea irradiate a region of the epithelial layer with a pulsed beam of ablative radiation. The ablative radiation is scanned to vary the location of the beam within the region in accordance with a pulse sequence. The pulse sequence is arranged to enhance optical feedback based on a tissue fluorescence of the epithelial layer. The penetration of the epithelial layer is detected in response to the optical feedback. The use of scanning with the pulse sequence arranged to enhance optical feedback allows large areas of the epithelium to be ablated such penetration of the epithelial layer can be detected.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part and claims the benefit ofU.S. application Ser. No. 11/937,760 filed Nov. 9, 2007, entitled“OPERATOR CONTROLLED SCANNING LASER PROCEDURE DESIGNED FOR LARGE-AREAEPITHELIAL REMOVAL,” which claims the benefit under 35 USC 119(e) ofU.S. Provisional Application No. 60/865,342 filed Nov. 10, 2006,entitled “OPERATOR CONTROLLED SCANNING LASER PROCEDURE DESIGNED FORLARGE-AREA EPITHELIAL REMOVAL,” the full disclosures of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention is generally related to correcting optical errorsof light refracted by eyes. In exemplary embodiments, the inventionprovides devices, systems, and methods for correction of optical errorsof eyes, and is particularly well suited for the treatment of eyesduring photorefractive keratectomy (PRK) and the like.

Known laser eye surgery procedures generally employ an ultraviolet orinfrared laser to remove a microscopic layer of stromal tissue from thecornea of the eye. The laser typically removes a selected shape of thecorneal tissue, often to correct refractive errors of the eye.Ultraviolet laser ablation results in photodecomposition of the cornealtissue, but generally does not cause significant thermal damage toadjacent and underlying tissues of the eye. The irradiated molecules arebroken into smaller volatile fragments photo-chemically, directlybreaking the intermolecular bonds.

Laser ablation procedures can remove the targeted stroma of the corneato change the cornea's contour for varying purposes, such as forcorrecting myopia, hyperopia, astigmatism, and the like. Control overthe distribution of ablation energy across the cornea may be provided bya variety of systems and methods, including the use of ablatable masks,fixed and moveable apertures, controlled scanning systems, eye movementtracking mechanisms, and the like. In known systems, the laser beamoften comprises a series of discrete pulses of laser light energy, withthe total shape and amount of tissue removed being determined by theshape, size, location, and/or number of laser energy pulses impinging onthe cornea. A variety of algorithms may be used to calculate the patternof laser pulses used to reshape the cornea so as to correct a refractiveerror of the eye. Known systems make use of a variety of forms of lasersand/or laser energy to effect the correction, including infrared lasers,ultraviolet lasers, femtosecond lasers, wavelength multipliedsolid-state lasers, and the like. The lasers of these laser systemstypically deliver a series of laser beam pulses during a treatment.

Known corneal correction treatment methods have generally beensuccessful in correcting standard vision errors, such as myopia,hyperopia, astigmatism, and the like. By customizing an ablation patternbased on wavefront measurements, it may be possible to correct minoraberrations so as to reliably and repeatedly provide visual acuitygreater than 20/20. Such detailed corrections will benefit from anextremely accurate ablation of tissue.

With laser ablation procedures, the epithelium is generally removed sothat the permanent optical correction can be ablated into the stroma.With PRK the epithelium is removed to expose Bowman's membrane.Epithelial removal has been accomplished mechanically and with laserablation of the epithelial layer. Mechanical removal of the epitheliallayer can be accomplished with mechanical scraping of the epithelialtissue layer to expose Bowman's membrane. Another mechanical approach isto remove the epithelium with a brush. With Laser-AssistedSub-Epithelial Keratectomy (LASEK), the epithelial layer is removed fromthe cornea as a sheet so that the layer can be replaced following theablation of stromal tissue. Although these mechanical methods ofepithelial removal have been successful clinically, mechanical removalof the epithelium takes time and can be perceived by the patients asinvasive because the surgeon will touch the front surface of the eyewith surgical instruments. Even though topical anesthesia is oftenapplied to the cornea so that the patient cannot feel the surgeontouching his or her cornea, the patient can become nervous while thesurgeon touches the front surface of the eye with the instruments,possibly delaying the procedure.

Laser ablation of the epithelium, also referred to as trans-epithelialablation, can be less invasive and faster than mechanical approaches toremoval of the epithelium. However, work in connection with the presentinvention suggests that the known methodologies for laser ablation ofthe epithelium may be less than ideal. Thus, a surgeon will oftenmechanically scrape the epithelium after laser removal of the epitheliumto ensure that no residual epithelial debris remains before ablatingstromal tissue.

In light of the above, it would be desirable to provide real-timemonitoring of trans-epithelial ablations over large areas of the corneawhile avoiding at least some of the limitations of known systems.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the present invention provide improved devices, systems,and methods for laser treatment, for example laser treatment of eyes.More specifically, embodiments of the present invention can enhance theaccuracy and efficacy of laser eye surgical procedures with improvedremoval of the epithelium, for example the corneal epithelium. Thisimproved removal of the corneal epithelium can improve refractivesurgical procedures, for example PRK, and can be useful for thetherapeutic removal of corneal haze. While the system and methods of thepresent invention are described primarily in the context of a laser eyesurgery system for treating the cornea of the eye, it should beunderstood that the techniques described herein may be adapted for usein many additional ablation procedures.

Many embodiments use a scanning laser beam that ablates an area largerthan the beam and induces fluorescence of the ablated tissue layer, forexample the corneal epithelium. A sequence of pulses of the beam can bearranged to enhance optical feedback based on the tissue fluorescence sothat areas of the epithelium larger than the beam can be ablated andepithelial tissue penetration detected. The size and position of thepulse sequence can be arranged to overlap at least some the scanningpulses on a region smaller than the ablation, for example a centralregion, so that penetration of the epithelium can be detected by viewingthe region. Hence, enhanced optical feedback encompasses scanning pulseswith a size and position arranged to ablate an area larger than the beamand overlap the pulses on a region, or portion, of the ablated area sothat penetration of the epithelium can be detected by viewing theregion. In many embodiments an operator may view the region and stop theablation in response to the enhanced optical feedback, and in someembodiments and energy detector, such as a CCD camera, may view theregion ablated with a pulse sequence, for example a pulse sequencearranged to enhance optical feedback.

In a first aspect, embodiments provide a method for removing anepithelial layer disposed over a stromal layer in a cornea. A region ofthe epithelial layer is irradiated with a pulsed beam of ablativeradiation. The ablative radiation is scanned to vary the location of thebeam within the region in accordance with a pulse sequence. The pulsesequence is arranged to enhance optical feedback based on a tissuefluorescence of the epithelial layer. The penetration of the epitheliallayer is detected in response to the optical feedback.

In many embodiments, the pulse sequence is sorted to enhance the opticalfeedback. Stromal tissue can be ablated with an optical correction inresponse the penetration of the epithelial layer.

In many embodiments, the epithelial layer is ablated to a first depthand an additional sub-layer of epithelial tissue is ablated to a seconddepth in response to the optical feedback.

In specific embodiments, the size of the laser beam is constant whilethe region is irradiated until the penetration of the epithelium isdetected.

In another aspect, embodiments provide a method for removing anepithelial layer disposed over a stromal layer in a cornea. A region ofthe epithelial layer is irradiated with laser beam pulses of ablativeradiation. The ablative radiation is scanned to vary the location of thebeam pulses within the region. The beam is adjusted to at least onesmaller beam size and at least one larger beam size while the beam ispulsed and scanned over the region in accordance with a pulse sequencearranged to enhance optical feedback. The penetration of the epitheliallayer is detected based on tissue fluorescence from the larger sizedbeam.

In many embodiments, the irradiated region has a central region and anouter peripheral region. The adjustably sized beam can be sized andscanned so that several larger sized pulses comprise marker pulses thatoverlap, for example in the central region, such that the penetration ofthe epithelium is detected based on a decrease in fluorescence of thecentral region from the marker pulses.

In some embodiments, each of the marker pulses covers the central regionto provide a measurement signal from the central region. In specificembodiments, the distance across the central region is about 3 mm andeach marker pulse is at least about 3.5 mm across so that each markerpulse overlaps and covers the central region. The marker pulses thatcover the central region may be delivered at a rate of at least about 1Hertz to detect penetration of the epithelium.

In many embodiments, the larger beam size has a distance across of atleast about 3.5 mm and the smaller beam size has a distance across of nomore than about 2.5 mm. In specific embodiments, the adjustably sizedbeam is circular and the distance across comprises a diameter.

In many embodiments, the distance across the region is at least about 8mm, and pulses of the larger beam size can comprise at least about 10%,for example at least about 30%, of a total number of pulses deliveredbefore the penetration is detected.

In many embodiments, the penetration of the epithelium is detected by anoperator based on the visible fluorescence of the epithelial layerirradiated with the large sized pulse.

In some embodiments, the penetration of the epithelium may be detectedby an energy detector based on a fluorescence of the epithelial layerirradiated with the larger sized pulse.

In many embodiments, the adjustably sized beam is scanned and sized inaccordance with a pre-programmed sequence to vary the location and sizeof the beam.

In many embodiments, the adjustably sized beam repeatedly changes fromat least one smaller size to at least one larger size before thepenetration of the epithelium is detected so that the ablated layer ofepithelium is substantially uniform when the penetration of theepithelium is detected.

In many embodiments, the adjustably sized beam changes from at least onesmaller size to at least one larger size at least about three times, forexample five times, before the penetration of the epithelium isdetected. In some embodiments, the smaller beam size is no more thanabout 2.5 mm across and the larger size is at least about 3.5 mm across.In specific embodiments, the smaller size may be no more than about 1.75mm across and the larger size is at least 4 mm across.

In many embodiments, the adjustably sized beam changes from a smallersize to a larger size in correlation with an intended sub-layer ofepithelial tissue ablated. In some embodiments, the intended sub-layercorresponds to an upper portion of the epithelial layer, and theadjustably sized beam changes from the smaller size to the larger sizefor each additional sub-layer ablated with the adjustably sized laserbeam. In specific embodiments, a plurality of the additional sub-layersis ablated before the penetration of the epithelium is detected.

In many embodiments, the tissue fluorescence comprises auto-fluorescenceof the tissue that originates from excitation of the molecules of thetissue with the adjustably sized laser beam.

In many embodiments, the adjustably sized beam is sized to provide atleast one intermediate beam size having a cross sectional size betweenthe at least the smaller beam size and the larger beam size.

In many embodiments, the adjustably sized beam is repeatedly sized sothat the larger size comprises several beam sizes and the smaller sizecomprises several small beam sizes.

In another aspect, embodiments of the current invention provide a systemto ablate an eye to remove an epithelial layer of the eye. A lasergenerates a beam of an ablative radiation. A movable scan componentscans the laser beam over a region of the eye to ablate the epitheliallayer. A processor system, which comprises a tangible medium and memory,is coupled to the laser and the movable scan component. The processorsystem is configured to scan the beam within the region in accordancewith a pulse sequence arranged to enhance an optical feedback signalbased on a tissue fluorescence of the epithelial layer.

In many embodiments, the processor system is configured to sort thepulse sequence to enhance the optical feedback.

In many embodiments, the system further comprises at least one lens toform an optical image of the fluorescence that is visible to an operatorsuch that the operator can detect the penetration of the epitheliallayer based on the optical feedback signal.

In another aspect, embodiments of the current invention provide a systemto ablate an eye to remove an epithelial layer of the eye. The systemcomprises a laser to generate a beam of ablative radiation. A movablestructure is disposed along the laser beam path to adjust a size of thelaser beam to at least one smaller size and at least one larger size. Amovable scan component is configured to scan the laser beam over aregion of the eye to ablate the epithelial layer. A processor, whichincludes tangible medium and memory, is coupled to the laser, themovable structure, and the movable scan component. The processor isconfigured to ablate an epithelium with at one larger beam size and atleast one smaller beam size so that a penetration of the epithelium canbe detected based on a tissue fluorescence from the larger size of thebeam during a procedure.

In many embodiments, the system comprises at least one of a display or amicroscope to provide an image of the tissue fluorescence to an operatorso that the operator can detect the penetration of the epithelium.

In some embodiments, the system may include an energy detector to detectthe penetration of the epithelium based on the fluorescence.

In many embodiments, the region of the eye comprises a central regionand an outer peripheral region. The processor is configured to overlapseveral pulses of at least one larger size of the beam in the centralregion to penetrate the epithelium in the central region. In someembodiments, the processor is configured to deliver the pulses with atleast one larger size beam to cover the central region to provide ameasurement signal from the central region. In specific embodiments, theprocessor can be configured to deliver pulses of the larger size beam(s)that cover the central region at a rate of at least about 1 Hertz todetect penetration of the epithelium from the measurement signal.

In many embodiments, the processor is configured to scan the laser beamover the region in accordance with a pre-programmed sequence to vary thesize and location of the beam. The processor may also be configured tovary between at least one smaller size and at least one larger size toablate the epithelium at substantially uniform rate. The processor mayalso be configured to vary the sized beam from at least one smaller sizeto at least one larger size in correlation with an intended sub-layer ofablated epithelial tissue.

In many embodiments, the small sized beam comprises a substantiallycircular beam with a diameter no more that about 2 mm across and thelarge sized beam is circular with a diameter at least about 4 mm across.

In many embodiments, the tissue fluorescence comprises anauto-fluorescence of the tissue that originates from excitation ofnaturally occurring molecules within tissue in which the molecules areexcited with the pulsed laser beam.

In many embodiments, the movable structure may comprise an irisdiaphragm, a plurality of apertures formed in a non-transmissivematerial or a lens.

In many embodiments, the movable scan component may comprise a movablemirror, a movable lens or a movable prism.

In another aspect, embodiments of the present invention provide a methodfor removing an epithelial layer disposed over a stromal layer in acornea. A region of the epithelial layer is irradiated with a pulsedbeam of an ablative radiation. The ablative radiation is scanned to varya location of the beam within the region in accordance with a pulsesequence. The pulse sequence is arranged in response to a plurality ofring shaped basis profiles.

In many embodiments, the ablative radiation is scanned in response to alinear combination of the plurality of ring shaped basis profiles.

In many embodiments, a first of the plurality of ring shaped basisprofiles is determined from a first pulse size scanned along a firstcircle, and a second of the plurality of ring shaped basis profiles isdetermined from a second pulse size scanned along a second circle. Thefirst circle and the second circle can be sized to align an outerboundary of the first ring shaped basis profile with an outer boundaryof the second ring shaped basis profile. The first pulse size and thesecond pulse size can be sized to align the outer boundary of the firstring shaped basis profile with the outer boundary of the second ringshaped basis profile.

In many embodiments, the pulse sequence is arranged in response to atleast one disc shaped basis profile in combination with the plurality ofring shaped basis profiles. The plurality of ring shaped basis profilesmay each comprise a central portion corresponding to no ablation, andthe at least one disc shaped basis profile may comprise a centralportion corresponding to a maximum depth of ablation of the at least onedisc shape basis profile.

In another aspect, embodiments of the present invention provide a systemto ablate an eye to remove an epithelial layer of the eye. The systemcomprises a laser to generate a beam of an ablative radiation. A movablestructure is disposed along the laser beam path to adjust a size of thelaser beam to at least one smaller size and at least one larger size. Amovable scan component is configured to scan the adjustably sized laserbeam over a region of the eye to ablate the epithelial layer. Aprocessor system comprises a tangible medium and a memory, and theprocessor system can be coupled to the laser, the movable structure andthe movable scan component. The processor system can be configured toscan the ablative radiation to vary a location of the beam in accordancewith a pulse sequence. The pulse sequence is arranged in response to aplurality of ring shaped basis profiles.

In many embodiments, the processor system is configured to scan theablative radiation in response to a linear combination of the pluralityof ring shaped basis profiles.

In many embodiments, the processor system is configured to determine afirst of the plurality of ring shaped basis profiles from a first pulsesize scanned along a first circle, and the processor system isconfigured to determine a second of the plurality of ring shaped basisprofiles is determined from a second pulse size scanned along a secondcircle. The processor system can be configured to size the first circleand the second circle to align an outer boundary of the first ringshaped basis profile with an outer boundary of the second ring shapedbasis profile. The processor system can be configured to size the firstpulse size and the second pulse size to align the outer boundary of thefirst ring shaped basis profile with the outer boundary of the secondring shaped basis profile.

In many embodiments, the processor system is configured to arrange thepulse sequence in response to at least one disc shaped basis profile incombination with the plurality of ring shaped basis profiles. Theprocessor system can be configured to store the plurality of ring shapedbasis profiles and each may comprise a central portion corresponding tono ablation. The processor system can be configured to store the atleast one disc shaped basis profile, and the disc shaped basis profilemay comprise a central portion corresponding to a maximum depth ofablation of the at least one disc shape basis profile.

In another aspect, embodiments of the present invention provide a systemto ablate an eye to remove an epithelial layer of the eye. The systemcomprises a laser to generate a beam of an ablative radiation. A movablescan component is configured to scan the laser beam over a region of theeye to ablate the epithelial layer. A sensor is configured to measurefluorescent light and generate a signal when the beam of ablativeradiation irradiates the eye. A processor system comprises a tangiblemedium and a memory, and the processor system is coupled to the laser,the movable scan component and the sensor. The processor system isconfigured to scan the beam of ablative radiation in response to thesignal.

In many embodiments, the sensor is configured to detect a first portionof the region and a second portion of the region, in which the firstportion comprises epithelium and the second portion comprises an exposedBowman's membrane. The processor system is configured to direct theablative laser beam toward the first portion and away from the portion.

In many embodiments, the sensor comprises an area configured to detectthe first region and the second region. The processor can be configuredto sample data from a part of the area in response to at least one of aposition of the eye, a position of the beam or a size of the beam. Thearea may comprise pixels and the part of the area may comprises a gridcomprising at least some of the pixels.

In many embodiments, the processor system is configured to detectpenetration of the epithelium in response to a first amount offluorescence and detect clearance of the epithelium in response to asecond amount of fluorescence, in which the second amount is smallerthan the first amount. The processor system can be configured togenerate a message to an operator in response to the detection ofpenetration and may stop firing of the laser in response to clearance ofthe epithelium.

In many embodiments, the sensor is synchronized with a trigger signal toacquire an image of fluorescent light for each pulse of the beam, andthe sensor is coupled to a display to display each image to an operatorin real time. The sensor can be configured to acquire each image with anelectronic shutter open for no more than about 1000 us, for example nomore than about 100 us.

In another aspect, embodiments of the present invention provide a methodablating an eye to remove an epithelial layer of the eye. A beam of anablative radiation is generated. The laser beam is scanned over a regionof the eye to ablate the epithelial layer. A signal is generated with afluorescent light sensor in response to the beam of ablative radiationthat irradiates the eye. The beam of ablative radiation is scanned inresponse to the signal.

In many embodiments, the sensor detects a first portion of the regioncomprising epithelium and a second portion of the region comprising anexposed Bowman's membrane, and the ablative laser beam is directedtoward the first portion and away from the second portion.

In many embodiments, penetration of the epithelium is detected inresponse to a first amount of fluorescence and clearance of theepithelium is detected in response to a second amount of fluorescence,in which the second amount is smaller than the first amount. A messageto an operator can be generated in response to the detection ofpenetration and firing of the laser can be stopped in response toclearance of the epithelium.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a laser ablation system forincorporating the invention;

FIG. 1A illustrates an ablation of an epithelial layer of an eye using aseries of scanning laser beam pulses of varying diameter applied over aregion of a cornea of an eye, according to embodiments of the presentinvention;

FIGS. 2 and 3 schematically illustrate a laser beam delivery system forselectively directing a laser beam onto the corneal tissue, according toembodiments of the present invention;

FIG. 4 is a function block diagram illustrating a control architectureof an ablation system as in FIG. 1;

FIG. 5A shows an epithelial ablation profile of an ablated region of anepithelial layer, according to embodiments of the present invention;

FIG. 5B shows a portion of a sequence of scanning laser beam pulses toused ablate the epithelial layer with the profile of FIG. 5A, in whichthe pulses are sized and positioned so as to permit detection of apenetration of the epithelial layer, according to embodiments of thepresent invention;

FIG. 5C shows penetration of the epithelial layer with a marker pulse ofthe sequence as in FIG. 5B, according to embodiments of the presentinvention;

FIG. 5D shows a display visible to a system operator in which theoperator can detect penetration of the epithelial layer with the pulsesof FIGS. 5B and 5C, according to the embodiments of the presentinvention;

FIG. 6A illustrates theoretical ablation profiles that can be attainedupon penetration of the epithelium, according to embodiments of thepresent invention;

FIG. 6B shows a timing diagram illustrating pulse count, approximateaverage ablation depth and adjusted laser beam diameter while the laserbeam pulses ablate tissue with profiles as in FIG. 6A, according toembodiments of the present invention;

FIG. 7A shows bulk ablation of a first portion of an epithelial layerand incremental step ablation of additional sub-layers of epithelialtissue, according to embodiments of the present invention;

FIG. 7B shows a timing diagram illustrating approximate average ablationdepth and adjusted laser beam diameter while the laser beam pulsesablate a first portion of the epithelial layer and additional sub-layersof epithelial tissue as in FIG. 7A, according to embodiments of thepresent invention;

FIG. 8 shows a method of epithelial ablation, according to embodimentsof the present invention;

FIG. 9 shows a treatment table in accordance with an embodiment of thepresent invention;

FIG. 10 shows a method of generating a laser treatment table, accordingto embodiments of the present invention;

FIG. 10A1 shows an ablation ring corresponding to a basis shape, inaccordance with the method of FIG. 10;

FIG. 10A2 shows an ablation ring corresponding to a basis shape, inaccordance with the method of FIG. 10;

FIG. 10A3 shows an ablation disc corresponding to a basis shape, inaccordance with the method of FIG. 10;

FIG. 10B1 shows an ablation profile for each pulse of the ablation ringas in FIG. 10A;

FIG. 10B2 shows an ablation profile for each pulse of the ablation ringas in FIG. 10B;

FIG. 10B3 shows an ablation profile for each pulse of an ablation ringas in FIG. 10C;

FIG. 10C shows fitting of basis profiles from the ablation rings anddiscs as in FIGS. 10A, 10B and 10C to determine a linear combination ofbasis profiles;

FIGS. 11A to 11H show examples of images of epithelial fluorescence,according to embodiments of the present invention;

FIG. 12A shows a plot of image intensity for epithelium removal withimages as in FIGS. 11A to 11H;

FIG. 13A shows an image of epithelial fluorescence and a grid forlocation specific epithelium ablation, according to embodiments of thepresent invention;

FIG. 13B shows scanning with tables in response to the measuredfluorescence as in FIG. 13A; and

FIG. 14A shows a method of location specific epithelium ablation.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is particularly useful for enhancing the accuracyand efficacy of laser eye surgical procedures, such as photorefractivekeratectomy (PRK), phototherapeutic keratectomy (PTK), and the like.Preferably, the present invention can provide enhanced optical accuracyof refractive procedures and improved patient comfort during theprocedure by improving removal of the corneal epithelium. Hence, whilethe system and methods of the present invention are described primarilyin the context of a laser eye surgery system for treating a cornea ofthe eye, it should be understood the techniques of the present inventionmay be adapted for use in alternative ablation procedures.

The techniques of the present invention can be readily adapted for usewith existing laser systems. By providing a more rapid (and hence, maybe less prone to error) methodology for correcting optical errors of aneye, the present invention facilitates sculpting of the cornea so thattreated eyes may regularly receive a desired optical correction havingimproved vision with minimal discomfort to a patient.

As used herein a substantially constant power level encompasses a powerlevel that is stable to within about 25% of an average power level.

Referring now to FIG. 1, a laser eye surgery system 10 for incorporatingthe present invention includes a laser 12 that produces a laser beam 14.Laser 12 is optically coupled to laser delivery optics 16, which directslaser beam 14 to an eye of patient P. A delivery optics supportstructure (not shown here for clarity) extends from a frame 18supporting laser 12. An input device 20 is used to align laser system 10with patient P. A microscope 21 is mounted on the delivery opticssupport structure, the microscope often being used to image a cornea ofeye E. The laser eye surgery system 10 may include a display 23 thatprovides an image of eye E that is visible to the user. A video camera25 can be optically coupled to microscope 21 to provide an image of theeye E on the display as seen through the microscope. Microscope 21 maycomprise at least one lens to form an optical image of the tissuefluorescence that is visible to the operator such that the operator candetect penetration of the epithelial layer based on the opticalfeedback. In some embodiments, video camera 25 comprises a camerasensitive to visible light and at least a portion of the epithelialfluorescence comprises visible light, such that epithelial fluorescencecan be seen with video camera 25. In some embodiments, a second videocamera 25A can be coupled to microscope 21. Second camera 25A comprisesa sensor sensitive to UV light to detect epithelial fluorescence. Secondcamera 25A can be triggered off the laser fire signal, such that eachpulse of the treatment can be shown on the display, for examplefluorescence from individual pulse 23P. Second video camera 25A maycomprise an electronic shutter synchronized to the laser trigger suchthat the shutter is open for no more than about 1 ms, for example nomore than 100 us, or even no more than 50 us, when the laser fires toenhance visibility of the epithelial fluorescence. Although a microscopeis shown, in some embodiments a camera lens can be used to image thetissue fluorescence, such that the image of the tissue fluorescence canbe shown on the display. In various embodiments, the laser eye surgerysystem 10 includes at least some portions of a Star S3 Active Trak™Excimer Laser System and/or a STAR S4 IR™ Excimer Laser System withVariable Spot Scanning (VSS™) and WaveScan WaveFront® System availablefrom VISX, INCORPORATED of Santa Clara, Calif.

Laser eye surgery system 10 may comprise an eye tracker 19. Eye tracker19 may comprise, for example, an eye tracker as commercially availablein the Star S3 Active Trak™ Excimer laser system and/or the STAR S4 IR™Excimer Laser System with Variable Spot Scanning (VSS™). Eye tracker 19may comprise optical components microscope 21. The eye tracking systemmay comprise at least some optical components separate from themicroscope, for example as described in U.S. Pat. No. 6,322,216, thefull disclosure of which is incorporated herein by reference. Eyetracker 19 can be in communication with the embedded computer so as tooffset the position of the laser beam pulse in response to a measuredposition of the eye. The processor may comprise a processor system withat least one processor, for example a plurality of processors, such as aprocessor for tracking the eye, a processor to control the laser and atleast one processor to control positions of scanning elements, sensorsand laser firing. The processor system may comprise a distributedprocessor system with a first processor to calculate a treatment table,for example at a research facility, and a second processor, for exampleof the laser system, to ablate the eye with the treatment table from thefirst processor.

The display 23 may comprise windows to show images of the eye, forexample a first window 23W and a second window 23A. First window 23A canbe coupled to video camera 25 to show the image of the eye E as seenthrough the operating microscope. First window 23W may show structuresvisible to the operator, for example a reticule 23R, and the image ofthe eye including the iris and pupil. Video camera 23 may comprise acolor video camera to show a color image of the eye to the operator onthe display. Second window 23A can be coupled to second video camera25A. The second video camera 25A can be coupled to a frame grabber ofthe embedded processor to grab an image for each pulse of the lasertreatment and display the image from each pulse in window 23A of thedisplay, so as to minimized dropped frames and facilitate detection ofpenetration through the epithelium. The camera synchronized to the laserbeam pulse can improve epithelial fluorescence imaging and may be usedfor detection of penetration where the display is shown to an operatorand/or where the laser pulse firing is stopped automatically. Althoughreference is made to a video camera, the fluorescence sensor cancomprise many known sensors sensitive to fluorescence such as at leastone of an area sensor, a line sensor, a CCD array, a gated imageintensifier, photomultiplier tube, a photodiode, a phototransistor or acascade detector.

While the input device 20 is here schematically illustrated as ajoystick, it should be understood that a variety of input mechanisms maybe used. Suitable input mechanisms may include trackballs, touchscreens, or a wide variety of alternative pointing devices. Stillfurther alternative input mechanisms include keypads, data transmissionmechanisms such as an Ethernet, intranet, internet, a modem, or thelike.

Laser 12 generally comprises an excimer laser, ideally comprising anargon-fluorine laser producing pulses of laser light having a wavelengthof approximately 193 nm. The pulse of laser light typically has a fixedpulse duration having a full width half maximum (FWHM) of about 15 nanoseconds during a treatment. Laser 12 will preferably be designed toprovide a feedback stabilized fluence at the patient's eye, deliveredvia delivery optics 16. The present invention may also be useful withalternative sources of ultraviolet or infrared radiation, particularlythose adapted to controllably ablate the corneal tissue without causingsignificant damage to adjacent and/or underlying tissues of the eye. Thelaser system may include, but is not limited to, excimer lasers such asargon-fluoride excimer lasers (producing laser energy with a wavelengthof about 193 nm), solid-state lasers, including frequency multipliedsolid-state lasers such as flash lamp and diode pumped solid-statelasers. Exemplary solid state lasers include UV solid state lasers(approximately 193-215 nm) such as those disclosed in U.S. Pat. Nos.5,144,630 and 5,742,626; Borsuztky et al., “Tunable UV Radiation atShort Wavelengths (188-240 nm) Generated by Sum Frequency Mixing inLithium Borate”, Appl. Phys. 61:529-532 (1995), and the like. The laserenergy may comprise a beam formed as a series of discreet laser pulses.A variety of alternative lasers might also be used. Hence, although anexcimer laser is the illustrative source of an ablating beam, otherlasers may be used in the present invention.

Laser 12 and delivery optics 16 will generally direct laser beam 14 tothe eye E of patient P under the direction of a computer 22. Computer 22will often selectively adjust laser beam 14 to expose portions of thecornea to the pulses of laser energy so as to effect a predeterminedsculpting of the cornea and alter the refractive characteristics of theeye. In many embodiments, both laser 14 and the laser delivery opticalsystem 16 will be under computer control of processor 22 to effect thedesired laser sculpting process, with the processor effecting (andoptionally modifying) the pattern of laser pulses. The pattern of pulsesmay by summarized in machine readable data of tangible media 29 in theform of a treatment table, and the treatment table may be adjustedaccording to feedback input into processor 22 from an automated imageanalysis system (manually input into the processor by a system operator)in response to feedback data provided from an ablation monitoring systemfeedback system. Such feedback might be provided by integrating thewavefront measurement system described below with the laser treatmentsystem 10, and processor 22 may continue and/or terminate a sculptingtreatment in response to the feedback, and may optionally also modifythe planned sculpting based at least in part on the feedback.

Laser beam 14 may be adjusted to produce the desired sculpting using avariety of alternative mechanisms. The laser beam 14 may be selectivelylimited using one or more variable apertures. An exemplary variableaperture system having a variable iris and a variable width slit isdescribed in U.S. Pat. No. 5,713,892, the full disclosure of which isincorporated herein by reference. The laser beam may also be tailored byvarying the size and offset of the laser spot from an axis of the eye,as described in U.S. Pat. No. 5,683,379, and as also described inco-pending U.S. patent application Ser. No. 08/968,380, filed Nov. 12,1997; and Ser. No. 09/274,999 filed Mar. 22, 1999, the full disclosuresof which are incorporated herein by reference.

Still further alternatives are possible, including scanning of the laserbeam over a surface of the eye and controlling the number of pulsesand/or dwell time at each location, as described, for example, by U.S.Pat. No. 4,665,913 (the full disclosure of which is incorporated hereinby reference); using masks in the optical path of laser beam 14 whichablate to vary the profile of the beam incident on the cornea, asdescribed in U.S. patent application Ser. No. 08/468,898, filed Jun. 6,1995 (the full disclosure of which is incorporated herein by reference);hybrid profile-scanning systems in which a variable size beam (typicallycontrolled by a variable width slit and/or variable diameter irisdiaphragm) is scanned across the cornea; or the like. The computerprograms and control methodology for these laser pattern tailoringtechniques are well described in the patent literature.

Additional components and subsystems may be included with laser system10, as should be understood by those of skill in the art. For example,spatial and/or temporal integrators may be included to control thedistribution of energy within the laser beam, as described in U.S. Pat.No. 5,646,791, the disclosure of which is incorporated herein byreference. An ablation effluent evacuator/filter, and other ancillarycomponents of the laser surgery system which are not necessary to anunderstanding of the invention, need not be described in detail for anunderstanding of the present invention.

Processor 22 may comprise (or interface with) a conventional PC systemincluding the standard operator interface devices such as a keyboard, adisplay monitor, and the like. Processor 22 will typically include aninput device such as a magnetic or optical disk drive, an internetconnection, or the like. Such input devices will often be used todownload a computer executable code from a tangible storage media 29embodying any of the methods of the present invention. Tangible storagemedia 29 may take the form of a floppy disk, an optical disk, a datatape, a volatile or non-volatile memory, or the like, and the processor22 will include the memory boards and other standard components ofmodern computer systems for storing and executing this code. Tangiblestorage media 29 may optionally embody wavefront sensor data, wavefrontgradients, a wavefront elevation map, a treatment map, a cornealtopography map, a measurement of refraction of the eye, and/or anablation table.

An ablation of an epithelial layer eye using a series of pulses 14 a-14e of a scanning laser beam is illustrated in FIG. 1A. The series ofpulses are applied over a trans-epithelial ablation region 15 of acornea C of an eye E. As illustrated in FIG. 1A pulses 14 e and 14 doverlap. A dimension across pulse 14 c is smaller than a dimensionacross pulse 14 b. The series of pulses 14 a to 14 e are sequentiallyapplied to eye E in accordance with a treatment table listing thecoordinates and sizes of the laser beam for each pulse. An additionalablation procedure can then be ablated into the stromal corneal tissueto provide a refractive correction. In some embodiments, the epitheliumcan be ablated to remove corneal haze.

Referring now to FIG. 2, laser beam delivery system 16 for directinglaser beam 14 at eye E will often include a number of mirrors 30, aswell as one or more temporal integrators 32 which may even (or otherwisetailor) the energy distribution across the laser beam. Laser 12 willoften comprise an excimer laser as described above.

In the exemplary embodiment, a variable aperture 34 changes a diameterand/or slot width to profile laser beam 14, ideally including both avariable diameter iris and a variable width slot. A prism 36 separateslaser beam 14 into a plurality of beamlets, which may partially overlapon eye E to smooth edges of the ablation or “crater” from each pulse ofthe laser beam. Referring now to FIGS. 2 and 3, an offset module 38includes motors 40 which vary an angular offset of an offset lens 42,and which also change the radial orientation of the offset. Hence,offset module 38 can selectively direct laser beam 14 at a desiredlateral region of the cornea. A structure and method for using laserbeam delivery system 16 and offset module 38 are more fully described inU.S. Pat. Nos. 6,984,227; 6,331,177; 6,203,539; 5,912,775; and U.S. Pat.No. 5,646,791 the full disclosures of which are incorporated herein byreference.

Referring now to FIG. 4, a control system of a laser system 10 isschematically illustrated according to the principles of the presentinvention. A processor 22 enables precise control of laser system 10 tosculpt a surface shape specified in a laser treatment table 52. Aprocessor 22, which generally comprises a PC workstation, makes use of acomputer program stored on a tangible media 29 to generate treatmenttable 52. Processor 22 includes a library 44 of treatments and treatmenttables as described in U.S. Pat. No. 6,245,059; and U.S. Pat. No.7,077,838, the full disclosures of which are incorporated herein byreference. An embedded computer 58 within laser system 10 is inelectronic communication with the PC workstation. Alternatively, a PCworkstation may be embedded in the laser system and include an embeddedprocessor card in communication with the PC workstation for directingthe ophthalmic surgery. The eye tracker 19, as described above, can beconnected to embedded computer 58. Video camera 25 and second videocamera 25A can be optically coupled to microscope 21, as describedabove, and connected to display 23 to show images of the eye to thesurgeon and/or system operator.

Embedded computer 58 is in electronic communication with a plurality ofsensors 56 and a plurality of motor drivers 60. The motor drivers 60 arecoupled to the embedded computer 58 to vary the position andconfiguration of many of the optical components of the delivery optics16 according to treatment table 52. For example, first and secondscanning axis 62, 64 control the position of the offset lens to move thebeamlets over the surface of the cornea. Iris motor 66 controls thediameter of the overall beam, and in some cases, the length of lighttransmitted through a variable width slot. Similarly slot width driver68 controls the width of the variable slot. Slot angle driver 70controls rotation of the slot about its axis. Beam angle driver 72controls rotation of the beam as effected by a temporal integrator asdescribed above. Processor 22 issues a command for laser 12 to generatea pulse of the laser beam 14 after the various optical elements havebeen positioned to create a desired crater on eye E. Treatment table 52comprises a listing of all of the desired craters to be combined so asto effect a treatment therapy.

A timer 80 is located on an add on card of processor 22 and is aLab-PC-1200 model card having timers 8253/8254. The Lab-PC-1200 modelcard is available from National Instruments of Austin, Tex. In alternateembodiments, timer 50 is located externally to processor 22. The timer80 is controlled by a computer program of processor 22 and is adapted tomeasure time intervals. The laser 12 is electronically coupled toprocessor 22. Laser 12 fires upon a command issued from processor 22 inresponse to a time interval measured by timer 80. Processor 22 variesthe rate at which laser 62 fires during at least a portion of atreatment of an eye E.

FIG. 5A shows an ablation profile 107 of an ablation region 100 of anepithelial layer, according to embodiments of the present invention.Cornea C includes an epithelial layer 102 and a stromal layer 104. ABowman's membrane 103 is disposed between epithelial layer 102 andstromal layer 104. Ablation profile 107 can include a clearance region106 in which the epithelium is removed, and a transition zone 108 whichextends from clearance region 106 to the unablated regions of thecornea. Transition zone 108 can be annular and extend with a spline,linear fit, or other connecting shape between the unablated epitheliumand clearance region 106. Examples of shapes that can be used astransition zones are described in U.S. patent application Ser. No.10/100,231, filed Mar. 14, 2002, published as US 2003/0176855, the fulldisclosure of which is incorporated herein by reference. Clearanceregion 106 can include a diameter across 106D. To optimize the ablationpulse sequence, the ablation pulse sequence can be determined withfitting of the clearance region 106 without fitting of the transitionzone, which may comprise many shapes resulting from the fitting of thepulse sequence to the clearance region with the pulse instructionvector. Ablation profile 107 of ablation region 100 includes transitionzone 108 and can include a diameter 107D across ablated region 107. Thelaser can be programmed to ablate the epithelial layer with a series oflaser beam pulses in many ways, for example as described in U.S. Pat.No. 7,008,415, the full disclosure of which is incorporated herein byreference.

The characteristics of epithelial ablation profile 107 can be selectedand/or adjusted by the operator as desired, and input with a treatmentscreen shown on a display as described above. Clearance region 107 canbe selected and/or adjusted to many values, for example values fromabout 6.0 to about 9.5 mm. The maximum ablation zone can be about 2 mmgreater than the selected clearance zone to provide an annulartransition zone about 1 mm thick. In many embodiments, the width of theannular transition zone as defined from an inner circumference to anouter circumference can be selected to be from about 0.75 to 1.5 mm,although narrower sized transition zones may require addition smalllaser beam pulses, thereby potentially increasing treatment time. Largersized transition zones may provide faster tissue removal with largerpulses, although in some embodiments a larger transition zone can causethe ablation to encroach on the limbus. In some embodiments, the maximumablation width can be limited to about 12 mm. Alternatively oradditionally, the maximum ablation width can be based on physiologicmeasurements from a wavefront machine, topography machine, or theoperating microscope, such that the maximum ablation width is 1 mm lessthan the diameter of the limbus. The maximum depth of ablation can beabout 75 microns. The thickness of the epithelial layer can be thickerperipherally than centrally such that the epithelium has a meniscusshape and the operator and/or ablation algorithm can compensate for athicker peripheral epithelium. The thickness and optical power of theepithelium may also be related to the curvature of the cornea. Thecurvature of the cornea can be measured with a keratometer and/ortopography machine and the keratometer values can be input by theoperator and incorporated into the ablation algorithm.

FIG. 5B shows a portion of a sequence 120 of scanning laser beam pulsesto used ablate the epithelial layer with the profile of FIG. 5A, inwhich the pulses are sized and positioned so as to permit detection of apenetration of the epithelial layer, according to embodiments of thepresent invention. Although circular pulses are shown, many pulsegeometries can be used, for example a variable width slit and/orvariable diameter iris diaphragm, and the size of the pulse can refer toa dimension across the pulse, for example a dimension across a slit.Sequence 120 of scanning laser beam pulses can be applied to ablationregion 100. Ablation region 100 can include a center 112. Sequence 120includes individual laser beam pulses 120A to 120G. Laser beam pulses120A to 120G are sized and positioned in ablation region 100 accordingto a treatment table. A cross sectional size of each of pulses 120A to120G can refer to a cross sectional diameter of each of the pulses andposition of laser beam pulses 120A to 120G can refer to a position of acenter of each pulse in relation to center 112 of ablated region 100.Laser beam pulses 120A to 120D have a small cross sectional size, forexample less than about 2 mm. Laser beam pulses 120E to 120G have alarge cross sectional size, for example larger than about 3.5 mm. Thesequence of laser beam pulses can include additional sizes of laser beampulses, for example intermediate size pulses having a diameter greaterthan about 2 mm and less than about 3.5 mm. Laser beam pulses 120E to120G overlap and cover a central region 110.

Fluorescence from central region 110 can be monitored to detectpenetration of the epithelial layer. In many embodiments, thefluorescence that is monitored can comprise tissue auto-fluorescencethat results from native molecules of the epithelial layer that areexcited with the ablative laser radiation. In some embodiments, thefluorescence can include fluorescence that results from the excitationof a fluorescent dye applied to the epithelium, which fluoresces inresponse to excitation from the ablative laser radiation. Althoughoverlap is shown in the central region, the pulse sequence can bearranged to overlap and cover other locations of the ablation region,for example peripheral regions, such that optical feedback is enhancedin the peripheral regions where the pulses overlap.

The small size laser beam pulses can include several sizes of laser beampulses, and the large and intermediate size laser beam pulses can alsoinclude several sizes of laser beam pulses. For example, in manytreatments the small sized laser beam pulses will comprises severalpulses having a diameter from about 0.7 mm to about 2.5 mm, and thelarge size laser beam pulses will comprise several laser beam pulseshaving a diameter from about 3.5 to about 6.5 mm. In many embodiments,the laser beam pulses used to ablate the epithelial layer can includeseveral intermediate sized laser beam pulses having a diameter fromabout 2.5 to 3.5 mm. Small size laser beam pulses can be used to provideaccurate ablation of tissue and minimize residual error while medium andlarge pulses can provide faster tissue removal and permit the user tovisualize penetration of the epithelium. In preferred embodiments, smallpulses may be used initially followed by large pulses, although thepulse sequence can be sorted in many ways. In some embodiments, a laserbeam pulse with a particular size can include several simultaneouslygenerated overlapping laser beams, for example as described in U.S. Pat.No. 6,984,227, previously incorporated herein by reference.

The pulse sequence can be arranged to provide medium to large sizedlaser beam pulses that overlap in central region 110 to mark thepenetration of the epithelium based on a decrease in fluorescence uponpenetration of the epithelium. Auto-fluorescence of the epithelial layeris greater than the auto-fluorescence of the underlying stromal layer sothat the pulses in central region 110 appear bright initially due toauto-fluorescence of the epithelial layer. Upon penetration into thestromal layer and many instances upon penetration into Bowman'smembrane, the auto-fluorescence decreases rapidly so that penetration ofthe epithelium can be detected. In some embodiments, large laser beampulses can cover central region 110 so as to permit detection of thepenetration of the epithelium. Each of pulses 120E to 120G are sizedwith a diameter and positioned in ablated region 100 so that each ofpulses 120E to 120G covers central region 110. Thus, an operator viewingthe ablation of region 100 can detect penetration of the epitheliumvisually by observing central region 110 and monitoring the tissuefluorescence of central region 110 that results from the marker pulsesapplied to ablated region 100. In a preferred embodiment central region110 has a dimension across of about 3 mm, although central region 110can be from about 2 to 6 mm across. Also, although central region 110 isshown as circular, central region 110 can be hexagonal, triangular nornearly any other shape that can provide a central region in which thefluorescence pattern appears substantially uniform until the epitheliumis penetrated. In some embodiments, marker pulses can be applied tonon-central regions of the ablation region, for example to peripheralregions, such that penetration of the epithelium can be detectedperipherally with the marker pulses overlapping in the periphery of theablated region.

The use of large to medium size pulses to mark the penetration of theepithelium can be accomplished in any number of ways. Work in relationwith embodiments the present invention suggests that medium to largepulses applied to central region 110 with a frequency of at least about0.5 Hz can provide a sufficient visual stimulus for an operator todetect penetration of the epithelial layer based on tissueauto-fluorescence in the visible portion of the spectrum ofelectromagnetic radiation. The marker pulses can be repeated at manyfrequencies from about 0.5 Hz to about 50 Hz, so that an operator canreadily detect penetration of the epithelium based on theauto-fluorescence of the epithelium originating from the central regionwith the marker pulses. For example, in many embodiments, the markerpulses are repeated at a frequency of about 5 to 20 Hz. In preferredembodiments, about two to three marker pulses can be appliedsequentially at about 20 Hz and about 1 second later an additional twoto three marker pulses can be applied at about 20 Hz. Thus, the operatorcan readily visualize a penetrated region of the epithelium with markerpulses spaced no more than one second apart and applied with a frequencyof at least about 1 Hz. In many embodiments, large central marker pulsescan comprise at least about 5% of the total number of pulses used toablate the epithelium for example from 5 to 25% of the total number ofpulses delivered during ablation of the epithelium. The larger markerpulses may comprise from 5 to 50% of the total number of pulsesdelivered, for example 45%. In many embodiments, the large centralmarker pulses comprise at least about 10% of the total number of pulsesused to ablate the epithelium, for example from about 10 to 15% of thetotal number of pulses applied to ablated the epithelium.

FIG. 5C shows penetration of the epithelial layer with a marker pulse ofthe sequence as in FIG. 5B, according to embodiments of the presentinvention. Central region 110 is covered by pulse 120E. An epithelialfluorescence pattern 130A indicates where the epithelium has not beenpenetrated. A stromal and/or Bowman's fluorescence pattern 130Bindicates where the epithelium has been penetrated. Subsequent pulses120F and 120G cover central region 110 so that stromal and/or Bowman'sfluorescence pattern 130B has substantially the same shape and becomessomewhat larger. Because stromal and/or Bowman's fluorescence pattern130B has substantially the same shape with sequential pulses, stromaland/or Bowman's fluorescence pattern can be readily identified with themarker pulses to detect penetration of the epithelium. Prior topenetration of the epithelium, central region 110 has a substantiallyuniform fluorescence intensity which provides a substantially uniformfluorescence pattern within central region 110. Thus, an operator canreadily visualize the penetration of the epithelium based on the changein tissue fluorescence within central region 110.

FIG. 5D shows an optical image 140 of the eye with a fluorescencepattern that is visible to a system operator in which the operator candetect penetration of the epithelial layer with the pulses of FIGS. 5Band 5C, according to the embodiments of the present invention. Opticalimage 140 can be displayed on a computer display as described above. Inmany embodiments, optical image 140 can be seen by the operator throughan operating microscope as described above. Optical image 140 caninclude a reticule 142 for alignment of the ablation. Reticule 142 caninclude concentric circles 144A to 144C. In a preferred embodiment,reticule 144C corresponds to central region 110. The operator observesepithelial fluorescence 130A and can detect penetration of theepithelium based on the appearance of stromal and/or Bowman's ablationpattern 130B. In some embodiments, a detector, for example a CCD thatdetects optical image 140, can be used with the pulse sequences andoptical system as described herein to automate detection of theepithelial penetration and generate an automated optical feedbackcontrol signal in response to the penetration of the epithelium. Inthese embodiments, the detector that detects optical image 140 has aview of eye E. The sorted pulse sequences and optical feedback asdescribed herein can be incorporated into systems that automaticallydetect penetration of the epithelium to provide control signals, forexample as described in U.S. Pat. Nos. 6,293,939; 6,019,755; and U.S.Pat. No. 5,505,724; the full disclosures of which are incorporated byreference.

The operator can respond to the visual optical feedback signal in manyways. For example, the operator can terminate the ablation of theepithelium and proceed to ablate the stroma with a desired opticaland/or therapeutic correction. The ablation of the stroma can comprisean optical correction such as a wavefront ablation and/or a therapeuticablation such as the removal of corneal haze. In many embodiments, priorto stromal ablation and after detection of epithelial penetration, theoperator may respond to the detection of epithelial penetration byscraping the exposed surface to ensure that all epithelial material hasbeen removed so that any debris that may be present does not effect thestromal ablation process.

In embodiments where epithelial penetration is not detected with a firstsequence of pulses, the operator may respond to the optical feed backsignal by selecting additional pulses and/or sequence(s) to ablateadditional sub-layers of the epithelium. In some embodiments, forexample, once a first sequence of pulses corresponding to first ablationdepth, for example 50 um, has been applied, the optical feedback signalmay indicate that the epithelium has not been penetrated. In response,the operator may select ablation with an additional sequence of pulsescorresponding to ablation of an additional layer of epithelial tissue,for example 5 um, and ablate this additional layer of tissue whileobserving the ablation process optical feedback provided by the sortedpulses. This process can be repeated with additional sequences thatcorrespond to the ablation of additional layers, for example in 5 umincrements, until penetration is detected in the central region or atotal maximum allowed ablation depth, for example 70 um, has beenachieved. The first ablation depth corresponding to the first sequencecan be from about 30 to about 60 microns, for example 50 um as describedabove. The additional ablation depth(s) corresponding to the additionalsequence(s) can correspond to depths for each layer within a range fromabout 1 to about 10 microns, for example 5 um as described above. Theabove pulses sequences can be sorted to enhance optical feedback asdescribed above.

Again referring FIGS. 5C and 5D image processing software can be used toidentify and track the epithelial breakthrough spot and then directfollow on pulses to the outer area so as to expand the breakthrough spotwithout ablating the identified location where the epithelium has beenpenetrated. An annular wide beam, for example a half-annulus, and orannular scan patter can be used to keep firing on the non-breakthroughareas and continue giving optical feedback without hitting the exposedcentral area where the epithelium is penetrated.

FIG. 6A illustrates ablation profiles that can be attained uponpenetration of the epithelium, according to embodiments of the presentinvention. Upon detection of penetration of the epithelium, the operatorcan stop the laser ablation of the epithelial surface. Thus, it isdesirable that the ablated layer of epithelial tissue is smooth when theoperator terminates the ablation of the epithelial surface. Ablationprofile 150A shows a theoretical ablation profile that results from theoperator stopping the epithelial ablation when the epithelium ispenetrated at an average ablation depth of 30 microns. Ablation profile150B and ablation profile 150C show theoretical ablation profiles forepithelial ablations terminated at average ablation depths of 50 micronsand 70 microns respectively. Similar ablation profiles can be achievedfor ablations terminated at many depths between 30 and 70 microns.

The ablation algorithm can be designed to provide a sequence of pulseswhich provide a desired amount of smoothness, based on the purpose ofthe underlying stromal ablation. Ablation profiles 150A to 150C show asmooth central region that extends about 6 mm across from a radialposition of about −3 mm to a radial position of about +3 mm. The smoothcentral region corresponds to the ablated optical zone in which stromaltissue is ablated with a refractive optical correction. The smoothnessof the ablated epithelial shape can have an RMS value of about 3 um orless, for example 2 um, and a peak to valley roughness of about 10 um orless, 5 um or less. The rougher peripheral region corresponds to theablated transition zone as described above. As the transition zone isablated may not be used to provide optical correction of stromal tissue,the exactness of the epithelial ablation over the transition zone may beless critical. In some embodiments, the roughness of the ablatedtransition zone can have a peak to valley roughness of 20 um or less,for example 10 um or less. As the operator may interrupt the ablation atany time, the smoothness of an ablation that is interrupted in responseto penetration of the epithelium may be slightly rougher. To minimizethe roughness of ablations that are terminated upon penetration of theepithelium, the pulses are arranged accordingly to provide a smoothablation upon termination. Work in relation with embodiments of thepresent invention indicates that ablations terminated in response todetection of epithelial penetration can provide smooth surfaces, forexample ablation surface having roughness metrics approximately twicethose described for ablation to a predetermined depth.

FIG. 6B shows a timing diagram illustrating pulse count, approximateaverage ablation depth and adjusted laser beam diameter while the laserbeam pulses ablate tissue with profiles as in FIG. 6A, according toembodiments of the present invention. The timing diagram includes atreatment time 162 in seconds, a pulse number 164, an approximateaverage ablation depth 166, and an adjusted beam diameter 168 used toablate epithelial tissue.

For a laser with a nearly constant laser pulse firing rate, for example20 Hz, pulse number 164 is closely correlated with treatment time 162.Although pulse number 164 increases linearly with time, in manyembodiments it may be desirable to very the laser pulse firing rate bycontrolling a time delay between each pulse. The average depth ofablation is related to the treatment time and increases with increasingtreatment time. In general, the average depth of ablation proceeds at arate of about 1 micron per second, although slower rates can beclinically effective and acceptable.

A vertical line 169 shows adjusted beam diameter 168 for several pulses.As will be appreciated with reference to pulse number 164 and verticalline 169, vertical line 169 indicates the size of the laser beam forseveral pulses of the laser beam, for example about 20 pulses of thelaser beam from the 400th pulse to the 420th pulse of the sequence.Thus, each vertical line that corresponds to adjusted beam diameter 168represents several laser beam pulses of the same diameter, and theselaser beam pulses of the same diameter can be scanned to differentlocations over the ablation region in accordance with the coordinatereferences of the treatment table.

Adjusted laser beam diameter 168 varies during the ablation of theepithelium. Adjusted laser beam diameter 168 includes several diametersused to ablate the first 30 microns of tissue and these diameters areindicated by arrow 160A. As the epithelial tissue layer is usually noless than 30 microns thick, laser beam pulses of increasing diameter areused to ablate the first 30 microns of tissue. If the operatorterminates the ablation at a depth of 30 microns ablation profile 150Awill be smooth as shown above.

Adjusted laser beam diameter 168 includes several diameters used toablate epithelial tissue from an average depth of 30 microns to anaverage depth of 70 microns are indicated by arrow 160B and arrow 160C.As the epithelial tissue layer can be from 30 to 70 microns thick, laserbeam pulses of alternating and/or interleaved large and small sizes canbe used to ablate the epithelial tissue layer from 30 microns to 70microns. Arrow 160B shows beam sizes for ablation from a depth of 30 to50 microns, and arrow 160C shows ablation from a depth of 50 to 70microns. From 30 to 50 microns, large diameter marker pulses 170A areapplied to detect penetration of the epithelium, and small diameterpulses 170B are applied between marker pulses 170A to ensure that theablation profile is smooth when the operator terminates ablation of theepithelium at a depth based on the detected penetration. From 50 to 70microns, large diameter marker pulses 170C are applied to detectpenetration of the epithelium, and small diameter pulses 170D areapplied between marker pulses 170C to ensure that the ablation profileis smooth when the operator terminates ablation of the epithelium at adepth based on the detected penetration. If the operator terminates theablation at any average ablation depth from 30 microns to 70 microns,the ablation profile will be smooth as shown above. Large beam sizes areused to remove tissue rapidly and provide marker pulses as describedabove, and the small beam pulses are interleaved between the markerpulses to knock down any non-uniformities in the ablation pattern thatdevelop as the ablation proceeds.

FIG. 7A shows bulk ablation of a first portion 210 of an epitheliallayer and incremental step ablation of additional sub-layers 220A to220C of epithelial tissue, according to embodiments of the presentinvention. First portion 210 of the ablated epithelial tissue can have adepth of approximately 50 microns, which corresponds to a typicalthickness of the ablated epithelial layer. In some embodiments, theoperator can program the bulk portion to have a selectable depth in arange from about 20 to 70 microns, for example from about 25 to 60microns. Additional sub-layers 220A to 220C can be sequentially ablated.Additional sub-layers 222 can be ablated as needed until penetration ofthe epithelium is detected. Each additional sub-layer has a thickness ofapproximately 1 to 10 microns, for example about 5 microns. Uponcompletion of ablation of the bulk layer sequence, the operator canprogram the laser to ablate an additional sub-layer if penetration isnot detected with ablation by the bulk sequence.

FIG. 7B shows a timing diagram illustrating approximate average ablationdepth and adjusted laser beam diameter while the laser beam pulsesablate a first portion of the epithelial layer and additional sub-layersof epithelial tissue as in FIG. 7A, according to embodiments of thepresent invention. The timing diagram includes a treatment time 262 inseconds and an adjusted beam diameter 268 used to ablate epithelialtissue. Adjusted laser beam diameter 268 varies during the ablation ofthe epithelium. Adjusted laser beam diameter 268 includes severaldiameters used to ablate first portion 210 and these diameters areindicated by arrow 230. As the epithelial tissue layer is usually noless than 30 microns thick, first portion 210 often corresponds to anablation depth of 30 microns, and laser beam pulses of increasingdiameter are used to ablate first portion 210. When the operatorterminates the ablation, the ablation profile will be smooth as shownabove. In some embodiments, when an operator terminates the ablationduring ablation of a sub-layer of the epithelium, the laser may continuethe ablation until the ablation of the sub-layer is completed so thatthe ablation is uniform. Thus, it may be desirable to make thesub-layers thin so that the ablation of the entire sub-layer provides anacceptably thin ablation of the underlying stromal tissue and/orBowman's membrane.

Adjusted laser beam diameter 268 includes several diameters used toablated sub-layers 220A to 220C. As the epithelial tissue layer can befrom 30 to 70 microns thick, laser beam pulses of alternating and/orinterleaved large and small sizes can be used to ablate each of theepithelial tissue sub-layers 220A to 220C. Large diameter marker pulses270A can be applied to detect penetration of the epithelium, and smalldiameter pulses 270B can be applied between marker pulses 270B to ensurethat the ablation profile is smooth when the operator terminatesablation based on the detected penetration of the epithelial layer. Anarrow 242 indicates ablation of epithelial tissue with additionalsub-layers 222 at depths below those of sub-layers 220A to 220C. Largeand small pulses can be used to ablate each additional sub-layer so thatthe ablation is smooth when the operator terminates the epithelialablation in response to penetration of the epithelium.

It should be noted that although FIGS. 5B to 7B make reference toembodiments in which laser beams of varying size are used to ablate theepithelium, embodiments of the present invention can employ a fixeddiameter treatment beam to ablate the epithelium. Such embodiments canbe readily implemented on the VISX Star™ platform by constraining thetreatment table to provide a single fixed constant diameter laser beamduring the ablation of the epithelial. The treatment table can be sortedto provide enhanced optical feedback in the central region of theepithelial ablation. This sorting of predetermined fixed diameter laserbeam sequences can also be incorporated into laser systems such as thosedescribed in U.S. Pat. Nos. 6,635,051; 6,575,962; 6,090,110; and U.S.Pat. No. 5,827,264, the full disclosures of which are incorporatedherein by reference. Although these embodiments that employ a constantsize laser beam are within the scope and spirit of the presentinvention, work in relation with the present invention suggests that thevariable beam embodiments described herein can provide faster ablationswith improved optical feedback and improved ablation characteristics,for example smoother ablation surfaces with well defined transitionzones and well defined ablation boundaries. In addition or incombination, it should be noted that solid state lasers can also be usedto provide sorted ablation sequences with improved optical feedback.

FIG. 8 shows a method of epithelial ablation 300, according toembodiments of the present invention. A step 310 selects laserepithelial removal and treatment parameters. Example parameters includea clearance zone diameter, a total ablation diameter, and a bulkablation depth, for example 50 microns. A step 320 applies a bulkablation sequence of laser beam pulses. Although the bulk ablationsequence may take approximately 30 seconds, the bulk ablation treatmentmay take any reasonable time, for example any time from about 10 secondsto two minutes, for example about 45 seconds. A step 330 terminatesand/or pauses ablation of the epithelial layer in response to detectionof penetration of the epithelial layer and/or in response to completionof the bulk ablation sequence so that the epithelium has been uniformlyablated to the selected bulk ablation depth. If necessary, a step 360selects an additional step ablation sequence, for example a sequencethat ablates a 5 micron sub-layer of epithelial tissue. Step 330terminates and/or pauses ablation of the epithelium in response todetection of penetration of the epithelial layer and/or completion ofthe additional sub-layer ablated. Additional step sequences can beselected with step 360 and the ablation can be terminated and/or pausedat step 330 as many times as needed to detect penetration of theepithelium and/or a maximum ablation depth, for example 70 um. A step340 may clear the surface of remaining epithelial debris, for examplewith mechanical scraping if desired by the treating physician. In someembodiments, the physician may not scrape the eye and use a no touchablation procedure in which the epithelium is removed entirely withlaser ablation. A step 350 begins the stromal and/or Bowman's ablationprocedure, for example to correct refractive error of the eye such aswavefront aberrations.

It should be appreciated that the specific steps illustrated in FIG. 8provide a particular method of measuring ablation according to anembodiment of the present invention. Other sequences of steps may alsobe performed according to alternative embodiments. For example,alternative embodiments of the present invention may perform the stepsoutlined above in a different order. Moreover, the individual stepsillustrated in FIG. 8 may include multiple sub-steps that may beperformed in various sequences as appropriate to the individual step.Furthermore, additional steps may be added or removed depending on theparticular applications. One of ordinary skill in the art wouldrecognize many variations, modifications, and alternatives.

FIG. 9 shows a treatment table 900 in accordance with an embodiment ofthe present invention. Treatment table 900 includes several parametersto control the pulse size, location and delay for each pulse of thelaser beam. A pulse number 910 indicates the pulse number of thesequence. An estimated depth 920 corresponds to the estimated averageablation depth for each pulse number. An iris diameter 930 indicatesthat diameter of the laser beam on the eye for each pulse of the laserbeam. An x-coordinate 940 lists the x-coordinate location on the centerof the sized laser beam on the eye for each pulse of the laser beam. Ay-coordinate 950 lists the y-coordinate of the center of the sized laserbeam on the eye for each pulse of the laser beam. A delay 960 lists thedelay from the previous pulse for each pulse of the laser beam, so thatthe laser pulse repetition rate can be controlled for each pulse of thelaser beam. For example delay 960 listed as 50 ms corresponds to a laserfiring rate of 20 Hz, and delay 960 listed as 100 ms corresponds to alaser firing rate of 10 Hz. Appendix A, incorporated herein byreference, lists the entire treatment table 900 to an average ablationdepth of about 63 microns for about 1100 pulses.

While the present invention has been described with respect toparticular embodiments and specific examples thereof, it should beunderstood that other embodiments may fall within the spirit and scopeof the invention. The scope of the invention should, therefore, bedetermined with reference to the appended claims along with their fullscope of equivalents.

FIG. 10 shows a method 1000 of generating a laser treatment table.Method 1000 may generate useful laser beam pulses, and may comprisebasis shapes and/or target warping. Method 1000 can be implemented onthe processor and/or controller of the laser surgery system as describedabove. Method 1000 may be implemented with a processor system, forexample a processor system in which a first processor at a firstlocation determines treatment tables and a second processor at a secondlocation treats the patient with the table generated with the firstprocessor. A sequence of pulses of the beam can be arranged to enhanceoptical feedback based on the tissue fluorescence so that areas of theepithelium larger than the beam can be ablated and tissue penetrationdetected, for example with sorting and pulse sizes as described above.

A step 1010 specifies the desired ablation shape. While the desiredshape can be specified in many ways, the following ablation parametersmay be used. A clearance zone can be chosen, for example a 9 mmclearance zone. The clearance zone may comprise the ablation area whereit is intended for the epithelium to be removed. A maximum ablationdiameter can be chosen, for a 12 mm maximum ablation diameter. Themaximum ablation diameter may comprise the maximum diameter may comprisea dimension of the ablation over which tissue is ablated. The maximumablation diameter may comprise the clearance zone and an annularablation region, over which annular region epithelium may not becompletely removed. A depth of epithelium can be chosen, for 50 microns.A mean curvature of the cornea can be entered, for example based on akeratometry curvature of 45 Diopters. The desired ablation shape may becompensated in response to the keratometery and a cosine effect of thelaser ablation process, in which cosine effect the surface of the corneanormal vector deviates from a direction of propagation of the laserbeam, such that the localized fluence as the ablation may be reduced bythe absolute value of the cosine of the surface normal vector of thecornea with the direction of propagation of the laser beam. The targetshape can be generated by incorporating desired ablation dimensions, forexample ablation profiles along two dimensions, and compensating forcosine effect based on mean keratometry and/or corneal topography. Aprocessor that determines angles between a curved surface and a laserbeam is described in U.S. Pat. No. 7,083,609, the full disclosure ofwhich is incorporated herein by reference and may be suitable forcombination with embodiments of the present invention.

A step 1020 construct an ablation ring basis shape. For example, withlargest diameter pulse available on a laser, for example a 6.5 mmablation, an ablation ring basis shape is constructed. The largest sizeof 6.5 mm is merely an example, and the largest size can be 5.0 mm, 2.0mm or even 1.0 mm or less. The ablation ring basis shape may comprise ofthe sum of 100 identically sized pulses evenly spaced along a circularpath. The circular path can be concentric with the desired shape, andthe pulses can be positioned such that the edge of each pulse justtouches the edge of the ablation. In a specific embodiment, the pulsesmay lie along a circular path whose diameter is the ablation diameterminus the pulse diameter. For example, for a desired shape with anablation diameter of 12 mm, a ring of 6.5 mm pulses would be placed in acircle with a diameter of 12 mm−6.5 mm=5.5 mm.

A step 1030 repeat step 1020 for all sizes of pulses that may be usedfor the ablation. For example step 1020 can be repeated with for eachpulse diameter of approximately 6.0 mm, 5.5 mm, 5.0 mm, 4.5 mm, 4.0 mm,3.5 mm, 3.0 mm, 2.5 mm, 2.0 mm, 1.5 mm, 1.0 mm and 0.5 mm. Although 0.5mm increments are listed, the increment may comprise many values fromabout 0.1 to 6 mm available with the laser system, for exampleincrements of 0.25 mm. The set of ablation ring shapes determined ateach increment may comprise basis shapes.

A step 1040 determines a linear combination of ablation ring shapes toapproximate the desired ablation shape, for example a weighting factorfor each shape. The linear combination of these ablation ring shapesthat best approximates the desired shape can be determined in many ways,for example with computerized optimization such as least squares fittingand/or simulated annealing. Generating laser scanning spot locations forlaser eye surgery is described in U.S. Pat. No. 7,008,415, the fulldisclosure of which has been incorporated herein by reference, and thedisclosure of this patent may be suitable for combination with someembodiments of the present invention. The liner combination may comprisea weighting factor for each ring, the weighting factor determined foreach ring may describe the number pulses to place in that ring. Theweighting factors may not be negative as ablation generally correspondsto removal of tissue. Any individual weighting factor may be greaterthan or equal to a threshold value, for example greater than or equal to0.2, to provide a threshold number of pulses per rind, for example atleast 20 pulses per ring. The algorithm may be biased toward using moreof the larger pulses than the smaller pulses, since the lager pulseshave a higher volume removal rate than smaller pulses.

A step 1050 assembles the treatment table. The table can be assembled byputting the determined number of pulses into each ring in response tothe linear combination and/or weighting factor. For example, thedetermined number of pulses may comprise the determined weighting factorof the ring times 100 pulses, for example when the basis shape isdetermined with 100 pulses. The table can be sorted such that the pulsesin each ring are evenly spaced along a circular path.

A step 1060 may sort the entire set of ablation pulses then sortedaccording to the following criteria: a) The ablation is divided intomultiple passes so that it progresses uniformly and so that the largepulses, whose fluorescence is easier to see, occur regularly throughoutthe entire ablation process; b) The pulses are sorted to minimizepulse-to-pulse overlap; this is done to try to minimize heat build-up;c) the pulse-to-pulse delays are minimized so as to minimize the overallablation time; this minimization may be constrained by corneal heatinglimits and may use the algorithm used to determined the linearcombinations.

It should be appreciated that the specific steps illustrated in FIG. 10provide a particular method of generating a laser treatment tableaccording to an embodiment of the present invention. Other sequences ofsteps may also be performed according to alternative embodiments. Forexample, alternative embodiments of the present invention may performthe steps outlined above in a different order. Moreover, the individualsteps illustrated in FIG. 10 may include multiple sub-steps that may beperformed in various sequences as appropriate to the individual step.Furthermore, additional steps may be added or removed depending on theparticular applications. One of ordinary skill in the art wouldrecognize many variations, modifications, and alternatives.

FIG. 10A1 shows an annular ablation ring corresponding to a first basisshape with a first pulse size. The annular ablation ring is formed withablation from a plurality of pulses having substantially the samediameter, for example 2.0 mm+/−0.2 mm. The plurality of pulses can beapplied with a center of each pulse along a circle, for example a firstcircle that corresponds to the clearance zone. The pulse center circleand pulse diameter are sized such that the edge of each pulse ispositioned along a circular boundary of the ablation, for example anouter circle of the annular ablation pattern. The outer boundary of theablation may have a diameter, for example of 10 mm.

FIG. 10A2 shows an ablation ring corresponding to a second basis shapewith a second pulse size. The annular ablation ring is formed withablation from a plurality of pulses having substantially the samediameter, for example 4.0 mm+/−0.2 mm. The plurality of pulses can beapplied with a center of each pulse along a circle, for example a secondcircle that positions the pulse centers inside the clearance zone. Thepulse center circle and pulse diameter are sized such that the edge ofeach pulse is positioned along a circular boundary of the ablation, asin FIG. 10A1. The outer boundary of the ablation may have a diameterthat matches the outer boundary of the first basis shape, for example 10mm.

FIG. 10A3 shows an ablation disc corresponding to an Nth basis shape.The Nth basis shape shows that several basis shapes can be formed, forexample annular and or discs, with increments of pulse size as describedabove. The ablation disc can be formed with ablation from a plurality ofpulses having substantially the same diameter, for example 6.0 mm+/−0.2mm. The plurality of pulses can be applied with a center of each pulsealong an Nth circle, for example a circle that positions the pulsecenters inside the clearance zone. The pulse center circle and pulsediameter can be sized such that the edge of each pulse is positionedalong a circular boundary of the ablation, as in FIGS. 10A1 and 10A2.The outer boundary of the ablation may have a diameter that matches theouter boundary of the first basis shape and second basis shape, forexample 10 mm.

FIG. 10B1 shows an ablation profile for each pulse of the ablation ringas in FIG. 10A. It may be desirable to determine the shape of tissueremoved with each pulse of the laser beam. Profile 1 shows the shapeprofile of tissue removed with each pulse of the laser beam for thefirst pulse size, for example the 2 mm pulse size, scanned with a centerof each pulse along a first circle. The shape profile of tissue removedwith each pulse of the laser beam can be determined for each pulsediameter. The shape of tissue removed with each pulse can be determinedbased on measured ablation profiles, for example as described in U.S.Pat. No. 6,302,876, the full disclosure of which is incorporated hereinby reference. The shape of tissue removed with each pulse can be summedover the ablation zone to determine the basis profile. For example theprofile of the 2 mm beam can be applied to over the ablation ring todetermine the shape of tissue removed with the ring, for example with100 pulses.

FIG. 10B2 shows an ablation profile for each pulse of the ablation ringas in FIG. 10B. Profile 2 shows the shape profile of tissue removed witheach pulse of the laser beam for the second pulse size, for example the4 mm pulse size, scanned with a center of each pulse along a secondcircle. The shape of tissue removed with each pulse can be summed overthe ablation zone to determine the second basis profile. For example theprofile of the 4 mm beam can be applied to over the second ablation ringto determine the shape of tissue removed with the ring, for example with100 pulses.

FIG. 10B3 shows an ablation profile for each pulse of an ablation ringas in FIG. 10C. Profile N shows the shape profile of tissue removed witheach pulse of the laser beam for the Nth pulse size, for example the 6mm pulse size, scanned with a center of each pulse along an Nth circle.The shape of tissue removed with each pulse can be summed over theablation zone to determine the second basis profile. For example theprofile of the 6 mm beam can be applied to over the Nth ablation todetermine the shape of tissue removed with the ablation, for examplewith 100 pulses.

FIG. 10C shows fitting of basis profiles from the ablation rings anddiscs as in FIGS. 10A, 10B and 10C to determine a linear combination ofbasis profiles. The basis profile B1 is determined from the firstablation ring from the first circular scan with a center of each pulsealong a first circle. The basis profile B2 is determined from the secondablation ring from the second circular scan with the center of eachpulse along the second circle. The basis profile Bn is determined fromthe Nth ablation from the Nth circular scan with the center of eachpulse along the second circle. The Epithelial Ablation profile comprisesa target epithelial ablation profile, for example a desired shape asdescribed above. The target epithelial ablation profile may comprise aclearance zone, for example with a removal zone with a dimension RZextending across the removal zone. The dimension AS extending across theentire ablation can correspond to the total ablation size. A transitionzone can extend from the outer boundary of the clearance zone to theouter boundary of the ablation zone.

The basis data are fit to the epithelial ablation profile to determine aliner combination of the basis data. To optimize the ablation pulsesequence, the ablation pulse sequence can be determined with fitting ofthe clearance region without fitting of the transition zone, which maycomprise many shapes resulting from the fitting of the pulse sequence tothe clearance region with the pulse instruction vector. In someembodiments, the transition zone may also be fit to determine the linearcombination, for example as described above. The liner combination ofbasis data comprises weights. A weight W1 comprises first weight of thelinear combination. First weight W1 can be used to determine the numberof pulses used with the first scan circle. For example with a firstweight of 0.23, 23 pulses may be used along the first circle. A secondweight W2 comprises second weight of the linear combination. Secondweight W2 can be used to determine the number of pulses used with thesecond scan circle. For example with a second weight of 0.47, 47 pulsesmay be used along the second circle. An Nth weight Wn comprises an Nthweight of the linear combination. Nth weight Wn can be used to determinethe number of pulses used with the Nth scan circle. For example with anNth weight of 0.83, 83 pulses may be used along the Nth circle. Theabove values are merely illustrative of the method of obtaining values,and actual values obtained in accordance with the above described methodand/or system can be different.

FIGS. 11A to 11H show examples of images of epithelial fluorescence froma patient treatment. The images shown in FIGS. 11A to 11H can be sampledfrom a treatment, for example a treatment of 1600 pulses. To obtain theimages, a UV sensitive CCD camera can be mounted on the side of themicroscope beam splitter and used to image the fluorescing event of eachpulse, as described above. The camera may have its own frame-capturecard located in the system controller computer. A “fire laser” signal,for example TTL (5 volt) signal, can be sent to the camera to triggerframe capture with each pulse, as described above. The exposure of theimage may be timed such that the entire fluorescing event will becaptured. The exposure time may be limited to 100 μs to avoid capturingunwanted light, including reflections from the patient illumination androom lighting.

FIG. 11A shows a baseline image acquired when the laser is not fired andthere is no epithelial fluorescence. FIG. 11B shows epithelialfluorescence with a first pulse at a first location, in whichfluorescence extends across the first pulse location with an intensityabove a threshold value. FIG. 11C shows epithelial fluorescence with asecond pulse at a second location, in which fluorescence extends acrossthe second pulse location with an intensity above the threshold value.FIG. 11D shows epithelial fluorescence with a third pulse at a thirdlocation, in which fluorescence extends across the third pulse locationwith an intensity above the threshold value. FIG. 11E shows epithelialfluorescence with a fourth pulse at a fourth location, in whichfluorescence extends across the fourth pulse location with an intensityabove the threshold value. FIG. 11F shows epithelial fluorescence with afifth pulse at a fifth location, in which fluorescence extends across amajority of the area of the fifth pulse location with an intensity abovethe threshold value, and portions of the fifth pulse location comprisefluorescence intensity below the threshold value so as to indicatepenetration of the epithelium. FIG. 11G shows epithelial fluorescencewith a sixth pulse at a sixth location, in which fluorescence extendsacross a minority of the area of the sixth pulse location with anintensity above the threshold value, and portions of the sixth pulselocation comprise fluorescence intensity below the threshold value so asto indicate penetration of the epithelium. FIG. 11H shows epithelialfluorescence with a seventh pulse at a seventh location, in whichfluorescence extends across a minority of the area of the seventh pulselocation with an intensity above the threshold value, and portions ofthe seventh pulse location comprise fluorescence intensity below thethreshold value so as to indicate penetration of the epithelium.

The images shown in 11A to 11H comprise images sampled from a portion ofthe treatment, and similar images can be acquired from each pulse of thelaser treatment for the entire treatment, for example with the cameratriggered off the laser and coupled to the frame grabber and shown onthe display as described above. The image from each pulse can be shownon the display in real time, such operator is able to visualizepenetration of the epithelium with minimal interference from visiblelight, for example as shown in FIG. 11A which shows little interferencefrom visible light at baseline.

Plotting General Intensity of Epithelial Fluorescence

FIG. 12A shows a plot of image intensity for epithelium removal withimages as in FIGS. 11A to 11H. This plot illustrates characteristics ofthe fluorescence images obtained with the above described system thatcan be used to detect penetration and/or clearance of the epithelium.Penetration/breakthrough of the epithelium can encompass at least someportion of the treatment area over which the epithelium which has beencompletely removed. Clearance of the epithelium may encompass removal ofthe epithelium over a majority of the surface area of the area targetedfor removal. In many embodiments, penetration/breakthrough correspondsto a first amount of fluorescence and epithelial clearance correspondsto a second amount of fluorescence, the second amount smaller than thefirst amount.

The mean intensity value of a 20 pulse rolling average can be graphed toshow intensity drop with penetration and/or epi clearance. Each laserbeam pulse applied to the epithelium will fluoresce a certain thresholdamount. Although the stroma may fluoresce, this amount can besubstantially below the threshold amount. The amount of epithelialfluorescence can be quantified by summing the brightness value of eachimage for an empirical number of patients, for example 20 patients. Aseach pulse is applied, a specific image intensity can be expectedbecause the exact area of epithelium irradiated is known based on theprogrammed size of the laser beam. By plotting the fluorescence valuesfor each pulse, for example expected fluorescence minus measured, on asimple line graph inflexion points can signify breakthrough/penetrationand clearance areas where epithelium has been removed. A running averageof fluorescence values for a plurality of pulses may be used todetermine penetration and/or clearance of the epithelium, for example arunning average of 20 pulses. Therefore, a signal indicated epithelialpenetration and/or clearance can be generated in response to at leastone the laser beam size, a mean expected fluorescence value or runningaverage of fluorescence. The signal may comprise a first signal toindicate penetration of the epithelium and a second signal to indicateclearance of the epithelium.

The physician can select among several modes of operation, for exampleamong 1) Automated detection of penetration and/or clearance with manualstopping of the laser; 2) Automated treatment stoppage; and 3) Locationspecific epithelium removal.

1. Automatic Detection of Epithelial Penetration and/or Clearance.

The penetration and/or clearance of the epithelium can be detected inmany ways based on the above described characteristics. In a specificexample, by performing a 20-pulse rolling average on all pulses with asignificant signal, for example 3.5 mm and above, an accurate inflectionpoint can be found and fed forward to the doctor. The detection ofepithelial penetration and/or clearance can be used to alert thephysician and/or to stop epithelial ablation in response to epithelialpenetration and/or clearance, for example based on images as describedabove. Because the patient's eye can move during surgery, an eye trackercan be used to monitor fluorescence automatically, and the centerlocation of the eye can be fed from the XY trackers continuously toimprove the quality of the sensor signal.

Physician Alerts

The decrease in fluorescence can trigger messages to the surgeon duringtreatment, for example alerting of initial breakthrough to stroma. Thephysician can stop the laser in response to the message, such thatdoctor can scrape the epithelium, for example with doctors who prefer toscrape residual epithelium. Once the doctor has scraped away residualepithelium, the doctor can continue with a refractive treatment withablation of the stroma to correct optical errors of the eye as describedabove. For surgeons preferring a “no-touch” approach without scraping ofthe residual epithelium, the system can signal when epithelium has beenpenetrated and/or cleared with ablation, and the physician can selectthe refractive treatment with ablation of the stroma to correct opticalerrors of the eye.

2. Automatic Treatment Stoppage.

In some embodiments, the fluorescence signal is used control the laserand to stop laser firing automatically, for example based on theinflexion points measured as described above. In addition to triggeringan alert, the system can stop at either the penetration/breakthroughamount or clearance amount, depending on what the surgeon had chosen,for example what the physician has selected prior to treatment. Forexample, a physician who scrapes the residual epithelium may select tostop the laser with penetration, and the physician who wishes to use ano touch procedure may select to stop the treatment with clearance ofthe epithelium.

3. Location Specific Ablation of Epithelium.

The real-time feedback of fluorescence imaging can control thepositioning of the laser pulses. As the epithelium is cleared away, thelaser can minimize, even avoid, ablation in those specific areas whereepithelium has been removed.

FIG. 13A shows an image of epithelial fluorescence and a grid forlocation specific epithelium ablation that can be used for locationspecific ablation. The image can be taken through a microscope, asdescribed above, and the image may comprise indicia used by thephysician during treatment. For example, a reticule can be used to showthe physician the center of treatment. A sub-grid, for example a redgrid can indicate the center of treatment. When the beam is scanned, thelaser beam may not be centered on the eye, for example when a 6.5 mmbeam is scanned and extends across a center of the ablation and an outerboundary of the clearance zone, as described above. A measurement gridcan extend across the image, with points on the grid shown to indicateto the physician the location of the grid. There can be a color encodedsub-grid, for example a rid grid, to indicate where measurements aretaken. There can be a series of images similar to FIG. 13A shown in realtime, so as to show the tracking of the red grid over the center of theeye. A couple of images of showing the recognition of stromalbreakthrough can be shown to the physician.

The optical imaging system can measure the fluorescence with a field ofview and resolution. The image field of view and resolution may comprisemany values. The image output may have resolution 640×480 pixels,although many resolutions may be used. At the distance of the camera,the field of view may be approximately 14.67×11.00 mm respectively,although the filed of view may comprise many angles.

The measurement grid can be used to sample data from the sensor array.Specific points can be measured on each image and brightness of thesepoints continually monitored for changes in intensity, for example achange from above a threshold to below a threshold so as to indicatepenetration of the epithelium. The points can be arranged in a squaregrid pattern, although many arrangements of points and/or lines can beused. For example the grid may comprise dimensions of 11×11 mm. The gridsample resolution may comprise about 500 micron spacing, for example 484points total, although many grid spacing and points can be used. Thisgrid sample area can cover an image area of the CCD camera sensor ofapproximately 480×480 pixels, and this amount of resolution allows oneto bin pixels at the grid location to measure intensity more accurately.For example, each sample point may comprise a nine pixel bin, in whichthe grid sample point comprises the average intensity value of thenine-pixel square. The use of the grid can reduce the processing time ofthe image as only part of the data from the CCD camera sensor is used.Each image can therefore be processed in real time to generate an arrayof intensity values comprising 484 points, although the array manycomprise many points and 484 is merely illustrative. Although referenceis made to a grid, other image processing techniques such as imagethreshold can be used to process the fluorescence images.

Data from the laser system and/or eye tracker can be used to process thefluorescence data from the fluorescence sensor to improve the accuracyof the measurements. For example, within the above described array, datasignals comprising the location of the eye, for example the centrallocation of the eye, can be fed forward from the tracker to theprocessor system. The processor system can be configured to select asubset of grid values, for example from a sub-grid, which can be usedfor analysis of the intensity values. This smaller array may measure,for example 7×7 mm and may comprise points of the grid, for example 196points. As the patients eye moves, the 7×7 mm array can move with theeye in response to eye position data from the eye tracker system. Forexample, the grid can stay centered on the eye and within the 11×11 mmgrid. The sub-grid can be adjusted in response to additional parametersof the laser treatment. For example, the sub-grid can be sized and/orshaped to correspond to the laser beam size and/or shape. The sub-gridcan change size and location with the beam size and location from thetreatment table. For example, the grid may comprise a circular gridsized to match the diameter of a circular pulsed laser beam. Thesub-grid can be moved with the laser beam as the beam scans over thetissue in response to the treatment table and eye tracker, such that thegrid is placed over the position of the beam and sized with the beam.For example, the laser beam may comprise a vertical height Wv and ahorizontal width Wh, and the sub-grid can be moved and sized with thebeam height Wv and beam width Wh. As the position of the beam is undercontrol of the processor, the position of the beam when the laser firescan be used to place the sub-grid over the beam in response to theposition of the beam deflection component. In some embodiments, themovable beam scan component may comprise a sensor that measures positionof the scan component, for example a galvanometer position sensor, suchthat sub-grid can be positioned on the beam in response to the measuredposition of the scan component.

The sub-grid can be sized to cover the optical zone. The optical zonecan comprise the portion of the ablation to correct an optical defect ofthe eye, for example myopia, and can be bounded by a transition zone.With an 7 mm optical zone the sub-grid may have a size of at least 7 mm.With an 8 mm optical zone treatment the sub-grid may extend at least 8mm across the fluorescence image. Values within the larger array but notwithin the sub-grid can be discarded.

Although reference is made to a sub-grid, many data sampling windows canbe sampled from a part the fluorescence image in response to at leastone of the position of the eye, the size of the laser beam, the shape ofthe laser beam, or a measured position of the beam scan component. Forexample, a spatial data sampling window can be used that corresponds toa part of the image and the part of the image selected for analysis inresponse to the position of the eye, the size of the laser beam, theshape of the laser beam and a measured position of the beam scancomponent.

The fluorescence data can be used to control the laser.

Real time intensity measurement of the fluorescence from the grid can beused to direct the laser beam. For example, 196 points can yield 196individual intensity profiles similar to the one found in FIG. 12A.Adjacent points of high intensity above a threshold can indicate aportion of the treatment area comprising remaining epithelium. Specifictables can be used to remove tissue in localized areas in response tothe number of adjacent points. The specific tables can be calculatedprior to treatment such that a table can be selected in response to atleast one of the area, location or shape of the fluorescence above thethreshold. For example a table can be selected in response to an area ofcoverage of the beam with the table and the area, the location and shapeof the fluorescence above the threshold. The small set of tables mayreside permanently on the laser and may be used only for epithelialablation. The tables can remove epithelium in many ways, for examplevarying degrees ablation over a circular area. As a safety mitigation,there can be limits to the amount of (depth) deviation allowed from aflat-bottomed ablation.

FIG. 13B shows scanning with tables in response to the measuredfluorescence as in FIG. 13A. The sub-grid can be analyzed to determineportions of the grid that are above threshold and portions belowthreshold so as to indicate the presence and penetration of theepithelium, respectively. A first table corresponding to an annular scanalong a first portion above threshold can be selected, for example anannular scan from about 9 o'clock to 12 o'clock can be selected. Asecond table can be selected corresponding to a second annular scanalong an arc, for example from about 2 o'clock to about 6 o'clock. Athird table corresponding to a first row scan can be selected. A fourthtable corresponding to a second row scan can be selected. A fifth tablecorresponding to a fifth scan can be selected. The treatment tables canbe stored in memory of the processor with coordinate references and beamsizes as described above.

FIG. 14A shows a method 1400 of location specific epithelium ablation.Method 1400 can be implemented with a processor system, for example aprocessor comprising a tangible medium configured to perform method1400. A step 1410 selects a treatment level, or operation mode. Thelevels can comprise: 1) an auto-detection level, 2) an auto-stop level;and 3) location specification ablation of epithelium. A step 1420generates an epithelium ablation table, for example as described above.The table may comprise a sequence of pulses of the beam that is arrangedto enhance optical feedback based on the tissue fluorescence so thatareas of the epithelium larger than the beam can be ablated and tissuepenetration detected, as described above. A step 1430 ablates theepithelium with the table. A step 1440 measures fluorescence, and thiscan be done in many ways as described above. A step 1450 detectspenetration and/or clearance of the epithelium.

A step 1451 can determine that level 1 has been selected. A step 1452displays an epithelial penetration message to the operator and/ordoctor. The epithelium penetration message can be displayed in responseto the fluorescence signal below a first threshold, as described above.A step 1453 stops the treatment, for example with a doctor removing afoot petal. A second message indicating epithelial clearance can also bedisplayed for the physician to stop the treatment when the epithelium iscleared with the laser ablation. A step 1490 ablates the stroma and/orBowman's with a refractive correction.

A step 1461 can determine that level 2 has been selected. A step 1462can display an epithelium penetration message. A step 1463 detectsclearance of the epithelium with ablation subsequent to penetration. Astep 1464 may stop the laser, for example to allow the physician toexamine the exposed surface to ensure the epithelium has been removed. Astep 1490 ablates the stroma and/or Bowman's with the refractivecorrection, for example in response to a physician depressing a footpetal after the laser has stopped.

A step 1471 can determine that level 3 has been selected. A step 1472displays the grid, for example as described above. A step 1473determines a position of the eye, for example with an eye tracker asdescribed above. A step 1474 determines the laser beam position, forexample as described above with reference to a beam scan component. Astep 1475 moves the grid. The grid can be moved in response to at leastone of the eye position, the beam position or the size of the beam. Astep 1476 measures fluorescence, for example with an array comprising agrid as described above. A step 1477 detects penetration of theepithelium, for example penetration for at least one measurement point.A step 1478 selects tables to ablate remaining epithelium, for exampletables as described above. A step 1479 ablates the epithelium with theselected tables. The above steps can be repeated until the epithelium iscleared. A step 1490 ablates the stroma and/or Bowman's with arefractive correction.

What is claimed is:
 1. A method for removing an epithelial layerdisposed over a stromal layer in a cornea, the method comprising:irradiating a region of the epithelial layer with a pulsed beam of anablative radiation; scanning the ablative radiation by moving a locationof the beam within the region in accordance with a pulse sequence,wherein the pulse sequence is arranged in response to a plurality ofepithelial layer ring shaped basis profiles, wherein at least some ofthe plurality of ring shaped basis profiles each comprise a centralportion corresponding to no ablation, wherein the pulsed beam of theablative radiation removes the epithelial layer to expose at least oneof the stromal layer or a bowman's membrane.
 2. The method of claim 1wherein a sequence of pulses of the beam is arranged to enhance opticalfeedback based on the tissue fluorescence so that areas of theepithelium larger than the beam can be ablated and epithelial tissuepenetration detected.
 3. The method of claim 1 wherein the ablativeradiation is scanned in response to a linear combination of theplurality of ring shaped basis profiles.
 4. The method of claim 1wherein a first of the plurality of ring shaped basis profiles isdetermined from a first pulse size scanned along a first circle andwherein a second of the plurality of ring shaped basis profiles isdetermined from a second pulse size scanned along a second circle. 5.The method of claim 4 wherein the first circle and the second circle aresized to align an outer boundary of the first ring shaped basis profilewith an outer boundary of the second ring shaped basis profile.
 6. Themethod of claim 5 wherein the first pulse size and the second pulse sizeare sized to align the outer boundary of the first ring shaped basisprofile with the outer boundary of the second ring shaped basis profile.7. The method of claim 1 wherein the pulse sequence is arranged inresponse to at least one disc shaped basis profile in combination withthe plurality of ring shaped basis profiles.
 8. The method of claim 7wherein the plurality of ring shaped basis profiles each comprise thecentral portion corresponding to no ablation and the at least one discshaped basis profile comprises a central portion corresponding to amaximum depth of ablation of the at least one disc shape basis profile.9. A method for removing an epithelial layer disposed over a stromallayer in a cornea, the method comprising: irradiating a region of theepithelial layer with a pulsed beam of an ablative radiation; scanningthe ablative radiation by moving a location of the beam within theregion in accordance with a pulse sequence, wherein the pulse sequenceis arranged in response to a plurality of epithelial layer ring shapedbasis profiles, wherein at least some of the ring shaped basis profileseach comprise a plurality of epithelial layer pulses, wherein at leastsome of the ring shaped basis profiles each comprise a central portioncorresponding to no ablation, wherein the pulsed beam of the ablativeradiation removes the epithelial layer to expose at least one of thestromal layer or a bowman's membrane.
 10. The method of claim 9, whereinthe plurality of pulses of at least one of the ring shaped basisprofiles are spaced along a circular path.
 11. The method of claim 10,wherein the plurality of pulses of the at least one ring shaped basisprofile each have a pulse center that lies on the circular path.
 12. Themethod of claim 9, wherein the plurality of pulses of at least some ofthe ring shaped basis profiles are each a plurality of circular pulsesspaced along a circular path.
 13. The method of claim 9, wherein thepulse sequence is arranged in response to the plurality of ring shapedbasis profiles and at least one disc shaped basis profile, and whereinthe disc shaped basis profile includes a central portion correspondingto an ablation region.
 14. A method for removing an epithelial layerdisposed over a stromal layer in a cornea, the method comprising:irradiating a region of the epithelial layer with a pulsed beam of anablative radiation; scanning the ablative radiation by moving a locationof the beam within the region in accordance with a pulse sequence,wherein the pulse sequence is arranged in response to a plurality ofepithelial layer ring shaped basis profiles and at least one epitheliallayer disc shaped basis profile, wherein at least some of the ringshaped basis profiles each comprise a plurality of circular pulsesaligned along a circular path and a central portion corresponding to noablation, wherein the disc shaped basis profile comprises a plurality ofcircular pulses aligned along another circular path, wherein the discshaped central portion includes a central portion corresponding to anablation region, wherein the pulsed beam of the ablative radiationremoves the epithelial layer to expose at least one of the stromal layeror a bowman's membrane, wherein outer boundaries of the ring and diskshaped basis profiles are coextensive.
 15. The method of claim 14,wherein the circular pulses of at least one of the ring shaped basisprofiles each have a pulse center that lies on the circular path of thering shaped basis profile.
 16. The method of claim 1, wherein at leastsome of the plurality of ring shaped basis profiles each comprise aplurality of pulses arranged on a circular path extending around thecentral portion corresponding to no ablation.
 17. The method of claim 1,wherein a plurality of pulses of at least one of the ring shaped basisprofiles are a plurality of pulses spaced along a circular pathextending around the central portion corresponding to no ablation. 18.The method of claim 1, wherein moving the location of the beam comprisesvarying an angular offset of an offset lens through which the beampasses.
 19. The method of claim 1 wherein the region is substantiallylarger than the beam, and wherein the pulse sequence is distributedwithin the region and arranged to enhance optical feedback from theregion based on a tissue fluorescence to facilitate selective removal ofthe epithelium by detecting and ablating residual epithelial tissuewithin the region.
 20. The method of claim 7, wherein the disc shapedbasis profile comprises a plurality of overlapping marker pulsesconfigured to indicate penetration of the epithelium.
 21. The method ofclaim 14, wherein the plurality of circular pulses of the disk shapedbasis profile are larger than the plurality of circular pulses of thering shaped basis profiles.
 22. The method of claim 21, wherein outerboundaries of the ring and disk shaped basis profiles align.
 23. Themethod of claim 21, wherein the ring and disk shaped basis profiles atleast partially overlap one another.